HEMATOLOGIC MALIGNANCIES PROGRAM ABSTRACT The overarching goal of the Hematologic Malignancies Program (HEM) is to advance the treatment of hematologic malignancies and reduce the side effects of treatment through the conduct of translational and clinical research performed by HEM members and collaborators. This will be accomplished by providing a clinically tractable understanding of somatic mutational, epigenetic, and proteomic drivers of myeloid and lymphoid neoplasm pathogenesis, using whole genome, epigenome, whole transcriptome and Nano- proteomic assays, and developing effective small molecule, biologic, and/or cellular therapies for patients that mitigate the risk of relapse. The program is led by Thomas Kipps (Professor, Medicine) a nationally recognized investigator in lymphoid malignancies, who founded the program, and Catriona Jamieson (Professor, Medicine) a cancer-stem-cell biologist focused on myeloid malignancies who joined Kipps in 2013 to broaden the program?s research scope and capabilities. HEM received an outstanding rating during the last CCSG renewal. The program?s scientific aims are to 1) use functional genomics, single cell transcriptomics, epigenetics, and proteomics to identify somatic DNA mutations, coding and non-coding RNA processing and ribosomal alterations in myeloproliferative neoplasms, myelodysplastic syndrome, leukemia, multiple myeloma, and lymphoma that promote therapeutic resistance and/or relapse, with a particular emphasis on cancer-stem- cell biology; 2) generate niche-relevant cell culture, transgenic, and/or humanized mouse models of pre- leukemia, leukemia, lymphoma, or myeloma to improve our understanding of the pathogenesis of disease, and validate somatic DNA, RNA processing alterations and aberrant signaling pathways as therapeutic targets; and 3) test promising new approaches in Phase l/ll clinical trials with pharmacokinetic and pharmacodynamics studies that examine whether the targeted molecular pathways are inhibited by therapy and establish surrogate endpoints for activity of novel therapeutic strategies for patients with myeloid or lymphoid malignancies, providing information for later-stage clinical trials. These aims align with the mission of the MCC, which is to mitigate the risk of developing cancer and improve the outcomes of patients with cancer within and beyond the catchment area; this represents a major focus of the strategic plan. The program?s 39 members represent 10 departments and 2 schools at UCSD, and 2 institutes: the La Jolla Institute (LJI) and The Scripps Research Institute (TSRI). In 2017, members had $15.4M (annual DC) in cancer-focused peer-reviewed funding of which $2.4M was from NCI; $13.0M was from other peer-reviewed agencies including other NIH sources and the California Institute for Regenerative Medicine (CIRM). During the project period, members have been involved in clinical translation of 5 Moores Cancer Center discoveries, authored 390 cancer-relevant publications, of which 63 (16%) were intra- programmatic, 76 (19%) were inter-programmatic, and 146 (37%) were collaborative with investigators from other NCI Cancer Centers.